Definition
Ataxia telangiectasia (A-T, OMIM #208900) is a disease which belongs to the group of DNA repair defects that play an important role in the regulation of central proteins of the signaling cascade between the identification and repair of DNA damage, including the tumor suppressor proteins p53, BRCA1, CHEK2, and NBS1. A-T is characterized by an increased sensitivity to ionizing radiation and by progressive neurological symptoms. NHL and ALL are of primary importance when it comes to a predisposition to cancer.
Key Data
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| Synonym | A-T |
| Gene | ATM (Ataxia telangiectasia mutated) |
| Gene product | Phosphatidylinsositol 3-kinase (PI3) protein family |
| Function | ATM kinase. The ATM mutation leads to a down-regulation of ATM kinase expression and function, resulting in a faulty DNA repair signaling cascade and an accumulation of DNA strand breaks, and results in genetic instability, specifically following exposure to ionizing radiation. |
| Heredity | Autosomal recessive |
| Prevalence | 1:40.000-1:100.000 |
| Genotype-phenotype correlation | c.5762-1050A>G slow neurological progression, later manifestation, intermediate radiosensitivity, risk of cancer increased slightly or not at all c.1A>G, c.7271T>G, c.8147T>C, c.8494C>T, etc. mild phenotype, longer survival, increased risk of cancer |
| Penetrance | High. Onset of initial neurological symptoms at the age of 2-4; most children need a wheelchair at 10 years of age. |
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Diagnosis
Indicative Findings
Abnormal newborn screening (for reduced T-cell receptor excision circle levels, TRECs)
Elevated AFP (alpha-fetoprotein)
Reduced IgA, IgE, and IgG2 levels (60-80%)
Poor antibody response to pneumococcal vaccines
Karyotype with t(7;14)-translocation (5-15%)
Cerebellar hypoplasia in the MRI
Increased sensitivity to ionizing radiation
Confirming the Diagnosis
Molecular genetic testing (single-gene or multiple-gene panel): Biallelic pathogenic ATM variant (homozygous or compound heterozygous)
Immunoblotting (ATM protein level reduced or not evident)
Differential Diagnoses
Nijmegen breakage syndrome (NBS)
MRE11 deficiency ataxia
RAD50 deficiency
RNF168 deficiency
Clinical Presentation
Typical A-T
Progressive cerebellar ataxia, starting between the 1st and 4th year of life
Conjunctival telangiectasia
Oculomotor apraxia
Choreoathetosis
Immunodeficiency
Tendency towards infections
Atypical A-T
A-T with the onset of spinal muscle atrophy during adulthood
A-T with early-onset dystonia
Other Findings
Premature aging with gray hairs
Endocrine abnormalities with the development of insulin-resistant diabetes mellitus and premature ovarian insufficiency
Associated Predisposition to Tumors
NHL
ALL
When there is heterozygosity (e.g. in the parents), an increased risk of mammary and ovarian carcinoma, gastric carcinoma, melanomas, leiomyomas, and sarcomas
Therapeutic Considerations
Avoid/reduce exposure to ionizing radiation and X-ray examinations if clinically acceptable.
The treatment of any neoplasia should be adjusted accordingly (reduced doses, longer treatment intervals) due to increased therapeutic toxicity, especially in children.
It is strongly recommended to test the parents whenever A-T is newly diagnosed, since there is also an increased risk of cancer in heterozygous carriers.
Surveillance Recommendations
Surveillance Recommendations
Evidence-based standards are lacking for tumor screening, particularly during childhood. The following are the recommendations from the AACR consensus meeting in October 2016.
Hematology-oncology: medical history, clinical examination, annual blood count, metabolic profile along with LDH (lactate dehydrogenase)
Immunology: monitoring of the immunoglobulin levels according to immunological recommendations
Dermatology: annual skin screening
Pulmonology: baseline examination, pulmonary function testing according to clinical need
Gastroenterology/nutrition: baseline examination, swallowing tests as needed, dietary supplementation
Endocrinology: annual diabetes screening
Neurology: supportive medication
Orthopedics: annual scoliosis evaluation
Dental: six-monthly checkups
Additional Information
Open Clinical Trials / Registries
ESID (European Society for Immunodeficiencies) Registry, Freiburg